C7 ester substituted taxanes

ABSTRACT

Taxanes having an ester substituent at C(7), a hydroxy substituent at C(10), and a range of C(2), C(9), C(14), and side chain substituents.

REFERENCE TO RELATED APPLICATION

This application claims priority from U.S. provisional applicationSerial No. 60/179,794, filed on Feb. 2, 2000.

BACKGROUND OF THE INVENTION

The present invention is directed to novel taxanes which haveexceptional utility as antitumor agents.

The taxane family of terpenes, of which baccatin III and taxol aremembers, has been the subject of considerable interest in both thebiological and chemical arts. Taxol itself is employed as a cancerchemotherapeutic agent and possesses a broad range of tumor-inhibitingactivity. Taxol has a 2′R, 3′S configuration and the followingstructural formula:

wherein Ac is acetyl.

Colin et al. reported in U.S. Pat. No. 4,814,470 that certain taxolanalogs have an activity significantly greater than that of taxol. Oneof these analogs, commonly referred to as docetaxel, has the followingstructural formula:

Although taxol and docetaxel are useful chemotherapeutic agents, thereare limitations on their effectiveness, including limited efficacyagainst certain types of cancers and toxicity to subjects whenadministered at various doses. Accordingly, a need remains foradditional chemotherapeutic agents with improved efficacy and lesstoxicity.

SUMMARY OF THE INVENTION

Among the objects of the present invention, therefore, is the provisionof taxanes which compare favorably to taxol and docetaxel with respectto efficacy as anti-tumor agents and with respect to toxicity. Ingeneral, these taxanes possess an ester substituent other than formate,acetate and heterosubstituted acetate at C-7, a hydroxy substituent atC-10 and a range of C-3′ substituents.

Briefly, therefore, the present invention is directed to the taxanecomposition, per se, to pharmaceutical compositions comprising thetaxane and a pharmaceutically acceptable carrier, and to methods ofadministration.

Other objects and features of this invention will be in part apparentand in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In one embodiment of the present invention, the taxanes of the presentinvention correspond to structure (1):

wherein

R₂ is acyloxy;

R₇ is R_(7a)COO—;

R_(7a) is hydrocarbyl, substituted hydrocarbyl, or heterocyclo whereinsaid hydrocarbyl or substituted hydrocarbyl contains carbon atoms in thealpha and beta positions relative to the carbon of which R_(7a) is asubstituent;

R₉ is keto, hydroxy, or acyloxy;

R₁₀ is hydroxy;

R₁₄ is hydrido or hydroxy;

X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl orheterocyclo;

X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀;

X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;

Ac is acetyl; and

R₇, R₉, and R₁₀ independently have the alpha or beta stereochemicalconfiguration.

In one embodiment, R₂ is an ester (R_(2a)C(O)O—), a carbamate(R_(2a)R_(2b)NC(O)O—), a carbonate (R_(2a)OC(O)O—), or a thiocarbonate(R_(2a)SC(O)O—) wherein R_(2a) and R_(2b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferredembodiment, R2 is an ester (R_(2a)C(O)O—), wherein R_(2a) is aryl orheteroaromatic. In another preferred embodiment, R₂ is an ester(R_(2a)C(O)O—), wherein R_(2a) is substituted or unsubstituted phenyl,furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R₂is benzoyloxy.

In one embodiment, R₇ is R_(7a)COO— wherein R_(7a) is (i) substituted orunsubstituted C₂ to C₈ alkyl (straight, branched or cyclic), such asethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted orunsubstituted C₂ to C₈ alkenyl (straight, branched or cyclic), such asethenyl, propenyl, butenyl, pentenyl or hexenyl; (iii) substituted orunsubstituted C₂ to C8 alkynyl (straight or branched) such as ethynyl,propynyl, butynyl, pentynyl, or hexynyl; (iv) substituted orunsubstituted phenyl; or (v) substituted or unsubstituted heteroaromaticsuch as furyl, thienyl, or pyridyl. The substituents may be hydrocarbylor any of the heteroatom containing substituents identified elsewhereherein for substituted hydrocarbyl. In a preferred embodiment, R_(7a) isethyl, straight, branched or cyclic propyl, straight, branched or cyclicbutyl, straight, branched or cyclic pentyl, straight, branched or cyclichexyl, straight or branched propenyl, isobutenyl, furyl or thienyl. Inanother embodiment, R_(7a) is substituted ethyl, substituted propyl(straight, branched or cyclic), substituted propenyl (straight orbranched), substituted isobutenyl, substituted furyl or substitutedthienyl wherein the substituent(s) is/are selected from the groupconsisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy,protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal,acetal, ester and ether moieties, but not phosphorous containingmoieties.

While R₉ is keto in one embodiment of the present invention, in otherembodiments R₉ may have the alpha or beta stereochemical configuration,preferably the beta stereochemical configuration, and may be, forexample, α- or β-hydroxy or α- or β-acyloxy. For example, when R₉ isacyloxy, it may be an ester (R_(9a)C(O)O—), a carbamate(R_(9a)R_(9b)NC(O)O—), a carbonate (R_(9a)OC(O)O—), or a thiocarbonate(R_(9a)SC(O)O—) wherein R_(9a) and R_(9b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R₉ is an ester(R_(9a)C(O)O—), R_(9a) is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstituted arylor substituted or unsubstituted heteroaromatic. Still more preferably,R₉ is an ester (R_(9a)C(O)O—), wherein R_(9a) is substituted orunsubstituted phenyl, substituted or unsubstituted furyl, substituted orunsubstituted thienyl, or substituted or unsubstituted pyridyl. In oneembodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) is methyl, ethyl, propyl(straight, branched or cyclic), butyl (straight, branched or cyclic),pentyl, (straight, branched or cyclic), or hexyl (straight, branched orcyclic). In another embodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) issubstituted methyl, substituted ethyl, substituted propyl (straight,branched or cyclic), substituted butyl (straight, branched or cyclic),substituted pentyl, (straight, branched or cyclic), or substituted hexyl(straight, branched or cyclic) wherein the substituent(s) is/areselected from the group consisting of heterocyclo, alkoxy, alkenoxy,alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro,amino, amido, thiol, ketal, acetal, ester and ether moieties, but notphosphorous containing moieties.

Exemplary X₃ substituents include substituted or unsubstituted C₂ to C₈alkyl, substituted or unsubstituted C₂ to C₈ alkenyl, substituted orunsubstituted C₂ to C₈ alkynyl, substituted or unsubstitutedheteroaromatics containing 5 or 6 ring atoms, and substituted orunsubstituted phenyl. Exemplary preferred X₃ substituents includesubstituted or unsubstituted ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.

Exemplary X₅ substituents include —COX₁₀, —COOX₁₀ or —CONHX₁₀ whereinX₁₀ is substituted or unsubstituted alkyl, alkenyl, phenyl orheteroaromatic. Exemplary preferred X₅ substituents include —COX₁₀,—COOX₁₀ or —CONHX₁₀ wherein X₁₀ is (i) substituted or unsubstituted C₁to C₈ alkyl such as substituted or unsubstituted methyl, ethyl, propyl(straight, branched or cyclic), butyl (straight, branched or cyclic),pentyl (straight, branched or cyclic), or hexyl (straight, branched orcyclic); (ii) substituted or unsubstituted C₂ to C₈ alkenyl such assubstituted or unsubstituted ethenyl, propenyl (straight, branched orcyclic), butenyl (straight, branched or cyclic), pentenyl (straight,branched or cyclic) or hexenyl (straight, branched or cyclic); (iii)substituted or unsubstituted C₂ to C₈ alkynyl such as substituted orunsubstituted ethynyl, propynyl (straight or branched), butynyl(straight or branched), pentynyl (straight or branched), or hexynyl(straight or branched); (iv) substituted or unsubstituted phenyl, or (v)substituted or unsubstituted heteroaromatic such as furyl, thienyl, orpyridyl, wherein the substituent(s) is/are selected from the groupconsisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy,protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal,acetal, ester and ether moieties, but not phosphorous containingmoieties.

In one preferred embodiment, the taxanes of the present inventioncorrespond to the following structural formula (2):

wherein

R₇ is R_(7a)COO—;

R₁₀ is hydroxy;

X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, orheterocyclo;

X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀;

X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;

R_(7a) is hydrocarbyl, substituted hydrocarbyl, or heterocyclo whereinsaid hydrocarbyl or substituted hydrocarbyl contains carbon atoms in thealpha and beta positions relative to the carbon of which R_(a) is asubstituent;

Bz is benzoyl; and

Ac is acetyl.

For example, in this preferred embodiment in which the taxanecorresponds to structure (2), R_(7a) may be substituted or unsubstitutedethyl, propyl or butyl, more preferably substituted or unsubstitutedethyl or propyl, still more preferably substituted or unsubstitutedethyl, and still more preferably unsubstituted ethyl. While R_(7a) isselected from among these, in one embodiment X₃ is selected fromsubstituted or unsubstituted alkyl, alkenyl, phenyl or heterocyclo, morepreferably substituted or unsubstituted alkenyl, phenyl or heterocyclo,still more preferably substituted or unsubstituted phenyl orheterocyclo, and still more preferably heterocyclo such as furyl,thienyl or pyridyl. While R_(7a) and X₃ are selected from among these,in one embodiment X₅ is selected from —COX₁₀ wherein X₁₀ is phenyl,alkyl or heterocyclo, more preferably phenyl. Alternatively, whileR_(7a) and X₃ are selected from among these, in one embodiment X₅ isselected from —COX₁₀ wherein X₁₀ is phenyl, alkyl or heterocyclo, morepreferably phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is alkyl, preferablyt-butyl. Among the more preferred embodiments, therefore, are taxanescorresponding to structure 2 in which (i) X₅ is —COOX₁₀ wherein X₁₀ istert-butyl or X₅ is —COX₁₀ wherein X₁₀ is phenyl, (ii) X₃ is substitutedor unsubstituted cycloalkyl, alkenyl, phenyl or heterocyclo, morepreferably substituted or unsubstituted isobutenyl, phenyl, furyl,thienyl, or pyridyl, still more preferably unsubstituted isobutenyl,furyl, thienyl or pyridyl, and (iii) R_(7a) is unsubstituted ethyl orpropyl, more preferably ethyl.

Among the preferred embodiments, therefore, are taxanes corresponding tostructure 1 or 2 wherein R₇ is R_(7a) COO— wherein R_(7a) is ethyl. Inthis embodiment, X₃ is preferably cycloalkyl, isobutenyl, phenyl,substituted phenyl such as p-nitrophenyl, or heterocyclo, morepreferably heterocyclo, still more preferably furyl, thienyl or pyridyl;and X₅ is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl,more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In onealternative of this embodiment, X₃ is heterocyclo; X₅ is benzoyl,alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl,t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is hydroxy and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is hydroxy and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is acyloxy and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is acyloxy and R₁₄ is hydrido. Ineach of the alternatives of this embodiment when the taxane hasstructure 1, R₇ and R₁₀ may each have the beta stereochemicalconfiguration, R₇ and R₁₀ may each have the alpha stereochemicalconfiguration, R₇ may have the alpha stereochemical configuration whileR₁₀ has the beta stereochemical configuration or R₇ may have the betastereochemical configuration while R₁₀ has the alpha stereochemicalconfiguration.

Also among the preferred embodiments are taxanes corresponding tostructure 1 or 2 wherein R₇ is R_(7a) COO— wherein R_(7a) is propyl. Inthis embodiment, X₃ is preferably cycloalkyl, isobutenyl, phenyl,substituted phenyl such as p-nitrophenyl, or heterocyclo, morepreferably heterocyclo, still more preferably furyl, thienyl or pyridyl;and X₅ is preferably benzoyl, alkoxycarbonyl, or heterocyclocarbonyl,more preferably benzoyl, t-butoxycarbonyl or t-amyloxycarbonyl. In onealternative of this embodiment, X₃ is heterocyclo; X₅ is benzoyl,alkoxycarbonyl, or heterocyclocarbonyl, more preferably benzoyl,t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is keto and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is hydroxy and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is hydroxy and R₁₄ is hydrido. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is acyloxy and R₁₄ is hydroxy. Inanother alternative of this embodiment, X₃ is heterocyclo; X₅ isbenzoyl, alkoxycarbonyl, or heterocyclocarbonyl, more preferablybenzoyl, t-butoxycarbonyl or t-amyloxycarbonyl, still more preferablyt-butoxycarbonyl; R₂ is benzoyl, R₉ is acyloxy and R₁₄ is hydrido. Ineach of the alternatives of this embodiment when the taxane hasstructure 1, R₇ and R₁₀ may each have the beta stereochemicalconfiguration, R₇ and R₁₀ may each have the alpha stereochemicalconfiguration, R₇ may have the alpha stereochemical configuration whileR₁₀ has the beta stereochemical configuration or R₇ may have the betastereochemical configuration while R₁₀ has the alpha stereochemicalconfiguration.

Taxanes having the general formula 1 may be obtained by treatment of aβ-lactam with an alkoxide having the taxane tetracyclic nucleus and aC-13 metallic oxide substituent to form compounds having a β-amido estersubstituent at C-13 (as described more fully in Holton U.S. Pat. No.5,466,834), followed by removal of the hydroxy protecting groups. Theβ-lactam has the following structural formula (3):

wherein P₂ is a hydroxy protecting group and X₃ and X₅ are as previouslydefined and the alkoxide has the structural formula (4):

wherein M is a metal or ammonium, P₁₀ is a hydroxy protecting group andR₂, R₉, R₇ and R₁₄ are as previously defined.

Alkoxide 4 may be prepared from 10-deacetylbaccatin III (or a derivativethereof) by selective protection of the C-10 hydroxyl group and thenesterification of the C-7 hydroxyl group followed by treatment with ametallic amide. In one embodiment of the present invention, the C(10)hydroxyl group of 10-deacetylbaccatin III is selectively protected witha silyl group using, for example, a silylamide or bissilyamide as asilylating agent. Preferred silylating agents includetri(hydrocarbyl)silyl-trifluoromethylacetamides and bistri(hydrocarbyl)-silyltrifluoromethylacetamides (with the hydrocarbylmoiety being substituted or unsubstituted alkyl or aryl) such asN,O-bis-(trimethylsilyl) trifluoroacetamide,N,O-bis-(triethylsilyl)trifluoroacetamide,N-methyl-N-triethylsilyltrifluoroacetamide, andN,O-bis(t-butyldimethylsilyl)trifluoroacetamide. The silylating agentsmay be used either alone or in combination with a catalytic amount of abase such as an alkali metal base. Alkali metal amides, such as lithiumamide catalysts, in general, and lithium hexamethyldisilazide, inparticular, are preferred. The solvent for the selective silylationreaction is preferably an ethereal solvent such as tetrahydrofuran.Alternatively, however, other solvents such as ether or dimethoxyethanemay be used. The temperature at which the C(10) selective silylation iscarried out is not narrowly critical. In general, however, it is carriedout at 0° C. or greater.

Selective esterification of the C(7) hydroxyl group of a C(10) protectedtaxane can be achieved using any of a variety of common acylating agentsincluding, but not limited to, substituted and unsubstituted carboxylicacid derivatives, e.g., carboxylic acid halides, anhydrides,dicarbonates, isocyanates and haloformates. For example, the C(7)hydroxyl group of the 10-protected-10-deacteyl baccatin III can beselectively acylated with dibenzyl dicarbonate, diallyl dicarbonate,2,2,2-trichloroethyl chloroformate, benzyl chloroformate or anothercommon acylating agent. In general, acylation of the C(7) hydroxy groupof a C(10) protected taxane are more efficient and more selective thanare C(7) acylations of a 7,10-dihydroxy taxane such as 10-DAB; statedanother way, once the C(10) hydroxyl group has been protected, there isa significant difference in the reactivity of the remaining C(7), C(13),and C(1) hydroxyl groups. These acylation reactions may optionally becarried out in the presence or absence of an amine base.

Derivatives of 10-deacetylbaccatin III having alternative substituentsat C(2), C(9) and C(14) and processes for their preparation are known inthe art. Taxane derivatives having acyloxy substituents other thanbenzoyloxy at C(2) may be prepared, for example, as described in Holtonet al., U.S. Pat. No. 5,728,725 or Kingston et al., U.S. Pat. No.6,002,023. Taxanes having acyloxy or hydroxy substituents at C(9) inplace of keto may be prepared, for example as described in Holton etal., U.S. Pat. No. 6,011,056 or Gunawardana et al., U.S. Pat. No.5,352,806. Taxanes having a beta hydroxy substituent at C(14) may beprepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.

Processes for the preparation and resolution of the β-lactam startingmaterial are generally well known. For example, the β-lactam may beprepared as described in Holton, U.S. Pat. No. 5,430,160 and theresulting enatiomeric mixtures of β-lactams may be resolved by astereoselective hydrolysis using a lipase or enzyme as described, forexample, in Patel, U.S. Pat. No. 5,879,929 Patel U.S. Pat. No. 5,567,614or a liver homogenate as described, for example, in PCT PatentApplication No. 00/41204. In a preferred embodiment in which theβ-lactam is furyl substituted at the C(4) position, the β-lactam can beprepared as illustrated in the following reaction scheme:

wherein Ac is acetyl, NEt₃ is triethylamine, CAN is ceric ammoniumnitrate, and p-TsOH is p-toluenesulfonic acid. The beef liver resolutionmay be carried out, for example, by combining the enatiomeric β-lactammixture with a beef liver suspension (prepared, for example, by adding20 g of frozen beef liver to a blender and then adding a pH 8 buffer tomake a total volume of 1 L).

Compounds of formula 1 of the instant invention are useful forinhibiting tumor growth in mammals including humans and are preferablyadministered in the form of a pharmaceutical composition comprising aneffective antitumor amount of a compound of the instant invention incombination with at least one pharmaceutically or pharmacologicallyacceptable carrier. The carrier, also known in the art as an excipient,vehicle, auxiliary, adjuvant, or diluent, is any substance which ispharmaceutically inert, confers a suitable consistency or form to thecomposition, and does not diminish the therapeutic efficacy of theantitumor compounds. The carrier is “pharmaceutically orpharmacologically acceptable” if it does not produce an adverse,allergic or other untoward reaction when administered to a mammal orhuman, as appropriate.

The pharmaceutical compositions containing the antitumor compounds ofthe present invention may be formulated in any conventional manner.Proper formulation is dependent upon the route of administration chosen.The compositions of the invention can be formulated for any route ofadministration so long as the target tissue is available via that route.Suitable routes of administration include, but are not limited to, oral,parenteral (e.g., intravenous, intraarterial, subcutaneous, rectal,subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal), topical (nasal, transdermal,intraocular), intravesical, intrathecal, enteral, pulmonary,intralymphatic, intracavital, vaginal, transurethral, intradermal,aural, intramammary, buccal, orthotopic, intratracheal, intralesional,percutaneous, endoscopical, transmucosal, sublingual and intestinaladministration.

Pharmaceutically acceptable carriers for use in the compositions of thepresent invention are well known to those of ordinary skill in the artand are selected based upon a number of factors: the particularantitumor compound used, and its concentration, stability and intendedbioavailability; the disease, disorder or condition being treated withthe composition; the subject, its age, size and general condition; andthe route of administration. Suitable carriers are readily determined byone of ordinary skill in the art (see, for example, J. G. Nairn, in:Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack PublishingCo., Easton, Pa., (1985), pp. 1492-1517, the contents of which areincorporated herein by reference).

The compositions are preferably formulated as tablets, dispersiblepowders, pills, capsules, gelcaps, caplets, gels, liposomes, granules,solutions, suspensions, emulsions, syrups, elixirs, troches, dragees,lozenges, or any other dosage form which can be administered orally.Techniques and compositions for making oral dosage forms useful in thepresent invention are described in the following references: 7 ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms 2nd Edition (1976).

The compositions of the invention for oral administration comprise aneffective antitumor amount of a compound of the invention in apharmaceutically acceptable carrier. Suitable carriers for solid dosageforms include sugars, starches, and other conventional substancesincluding lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar,mannitol, sorbitol, calcium phosphate, calcium carbonate, sodiumcarbonate, kaolin, alginic acid, acacia, corn starch, potato starch,sodium saccharin, magnesium carbonate, tragacanth, microcrystallinecellulose, colloidal silicon dioxide, croscarmellose sodium, talc,magnesium stearate, and stearic acid. Further, such solid dosage formsmay be uncoated or may be coated by known techniques; e.g., to delaydisintegration and absorption.

The antitumor compounds of the present invention are also preferablyformulated for parenteral administration, e.g., formulated for injectionvia intravenous, intraarterial, subcutaneous, rectal, subcutaneous,intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal routes. The compositions of theinvention for parenteral administration comprise an effective antitumoramount of the antitumor compound in a pharmaceutically acceptablecarrier. Dosage forms suitable for parenteral administration includesolutions, suspensions, dispersions, emulsions or any other dosage formwhich can be administered parenterally. Techniques and compositions formaking parenteral dosage forms are known in the art.

Suitable carriers used in formulating liquid dosage forms for oral orparenteral administration include nonaqueous,pharmaceutically-acceptable polar solvents such as oils, alcohols,amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, aswell as water, saline solutions, dextrose solutions (e.g., DW5),electrolyte solutions, or any other aqueous, pharmaceutically acceptableliquid.

Suitable nonaqueous, pharmaceutically-acceptable polar solvents include,but are not limited to, alcohols (e.g., α-glycerol formal, β-glycerolformal, 1,3-butyleneglycol, aliphatic or aromatic alcohols having 2-30carbon atoms such as methanol, ethanol, propanol, isopropanol, butanol,t-butanol, hexanol, octanol, amylene hydrate, benzyl alcohol, glycerin(glycerol), glycol, hexylene glycol, tetrahydrofurfuryl alcohol, laurylalcohol, cetyl alcohol, or stearyl alcohol, fatty acid esters of fattyalcohols such as polyalkylene glycols (e.g., polypropylene glycol,polyethylene glycol), sorbitan, sucrose and cholesterol); amides (e.g.,dimethylacetamide (DMA), benzyl benzoate DMA, dimethylformamide,N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide, 2-pyrrolidinone,1-methyl-2-pyrrolidinone, or polyvinylpyrrolidone); esters (e.g.,1-methyl-2-pyrrolidinone, 2-pyrrolidinone, acetate esters such asmonoacetin, diacetin, and triacetin, aliphatic or aromatic esters suchas ethyl caprylate or octanoate, alkyl oleate, benzyl benzoate, benzylacetate, dimethylsulfoxide (DMSO), esters of glycerin such as mono, di,or tri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate,ethyl carbonate, ethyl lactate, ethyl oleate, fatty acid esters ofsorbitan, fatty acid derived PEG esters, glyceryl monostearate,glyceride esters such as mono, di, or tri-glycerides, fatty acid esterssuch as isopropyl myristrate, fatty acid derived PEG esters such asPEG-hydroxyoleate and PEG-hydroxystearate, N-methyl pyrrolidinone,pluronic 60, polyoxyethylene sorbitol oleic polyesters such aspoly(ethoxylated)₃₀₋₆₀ sorbitol poly(oleate)₂₋₄, poly(oxyethylene)₁₅₋₂₀monooleate, poly(oxyethylene)₁₅₋₂₀ mono 12-hydroxystearate, andpoly(oxyethylene)₁₅₋₂₀ mono ricinoleate, polyoxyethylene sorbitan esterssuch as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitanmonopalmitate, polyoxyethylene-sorbitan monolaurate,polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80from ICI Americas, Wilmington, Del., polyvinylpyrrolidone, alkyleneoxymodified fatty acid esters such as polyoxyl 40 hydrogenated castor oiland polyoxyethylated castor oils (e.g., Cremophor® EL solution orCremophor® RH 40 solution), saccharide fatty acid esters (i.e., thecondensation product of a monosaccharide (e.g., pentoses such as ribose,ribulose, arabinose, xylose, lyxose and xylulose, hexoses such asglucose, fructose, galactose, mannose and sorbose, trioses, tetroses,heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactoseand trehalose) or oligosaccharide or mixture thereof with a C₄-C₂₂ fattyacid(s)(e.g., saturated fatty acids such as caprylic acid, capric acid,lauric acid, myristic acid, palmitic acid and stearic acid, andunsaturated fatty acids such as palmitoleic acid, oleic acid, elaidicacid, erucic acid and linoleic acid)), or steroidal esters); alkyl,aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether,tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethylether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycolether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethylketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatichydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane,dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane,sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene,dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral,vegetable, animal, essential or synthetic origin (e.g., mineral oilssuch as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons,mixed aliphatic and aromatic based hydrocarbons, and refined paraffinoil, vegetable oils such as linseed, tung, safflower, soybean, castor,cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ,sesame, persic and peanut oil and glycerides such as mono-, di- ortriglycerides, animal oils such as fish, marine, sperm, cod-liver,haliver, squalene, squalane, and shark liver oil, oleic oils, andpolyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbonatoms and optionally more than one halogen substituent; methylenechloride; monoethanolamine; petroleum benzin; trolamine; omega-3polyunsaturated fatty acids (e.g., alpha-linolenic acid,eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid);polyglycol ester of 12-hydroxystearic acid and polyethylene glycol(Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethyleneglycerol; sodium laurate; sodium oleate; or sorbitan monooleate.

Other pharmaceutically acceptable solvents for use in the invention arewell known to those of ordinary skill in the art, and are identified inThe Chemotherapy Source Book (Williams & Wilkens Publishing), TheHandbook of Pharmaceutical Excipients, (American PharmaceuticalAssociation, Washington, D.C., and The Pharmaceutical Society of GreatBritain, London, England, 1968), Modern Pharmaceutics, (G. Banker etal., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y., 1995), ThePharmacological Basis of Therapeutics, (Goodman & Gilman, McGraw HillPublishing), Pharmaceutical Dosage Forms, (H. Lieberman et al., eds.,)(Marcel Dekker, Inc., New York, N.Y., 1980), Remington's PharmaceuticalSciences (A. Gennaro, ed., 19th ed.)(Mack Publishing, Easton, Pa.,1995), The United States Pharmacopeia 24, The National Formulary 19,(National Publishing, Philadelphia, Pa., 2000), A. J. Spiegel et al.,and Use of Nonaqueous Solvents in Parenteral Products, JOURNAL OFPHARMACEUTICAL SCIENCES, Vol. 52, No. 10, pp. 917-927 (1963).

Preferred solvents include those known to stabilize the antitumorcompounds, such as oils rich in triglycerides, for example, saffloweroil, soybean oil or mixtures thereof, and alkyleneoxy modified fattyacid esters such as polyoxyl 40 hydrogenated castor oil andpolyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor®RH 40 solution). Commercially available triglycerides includeIntralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm,Sweden), Nutralipid® emulsion (McGaw, Irvine, Calif.), Liposyn® II 20%emulsion (a 20% fat emulsion solution containing 100 mg safflower oil,100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion(a 2% fat emulsion solution containing 100 mg safflower oil, 100 mgsoybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), natural or syntheticglycerol derivatives containing the docosahexaenoyl group at levelsbetween 25% and 100% by weight based on the total fatty acid content(Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro®(from Daito Enterprises, Los Angeles, Calif.), Soyacal®, andTravemulsion®. Ethanol is a preferred solvent for use in dissolving theantitumor compound to form solutions, emulsions, and the like.

Additional minor components can be included in the compositions of theinvention for a variety of purposes well known in the pharmaceuticalindustry. These components will for the most part impart propertieswhich enhance retention of the antitumor compound at the site ofadministration, protect the stability of the composition, control thepH, facilitate processing of the antitumor compound into pharmaceuticalformulations, and the like. Preferably, each of these components isindividually present in less than about 15 weight % of the totalcomposition, more preferably less than about 5 weight %, and mostpreferably less than about 0.5 weight % of the total composition. Somecomponents, such as fillers or diluents, can constitute up to 90 wt. %of the total composition, as is well known in the formulation art. Suchadditives include cryoprotective agents for preventing reprecipitationof the taxane, surface active, wetting or emulsifying agents (e.g.,lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylenestearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbialpreservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol,sorbic acid, thimerosal and paraben), agents for adjusting pH orbuffering agents (e.g., acids, bases, sodium acetate, sorbitanmonolaurate), agents for adjusting osmolarity (e.g., glycerin),thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol,stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose,tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes,flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g.,bentonites), adhesives, bulking agents, flavorings, sweeteners,adsorbents, fillers (e.g., sugars such as lactose, sucrose, mannitol, orsorbitol, cellulose, or calcium phosphate), diluents (e.g., water,saline, electrolyte solutions), binders (e.g., starches such as maizestarch, wheat starch, rice starch, or potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers,acacia), disintegrating agents (e.g., starches such as maize starch,wheat starch, rice starch, potato starch, or carboxymethyl starch,cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereofsuch as sodium alginate, croscarmellose sodium or crospovidone),lubricants (e.g., silica, talc, stearic acid or salts thereof such asmagnesium stearate, or polyethylene glycol), coating agents (e.g.,concentrated sugar solutions including gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide),and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodiumsulfite, dextrose, phenols, and thiophenols).

In a preferred embodiment, a pharmaceutical composition of the inventioncomprises at least one nonaqueous, pharmaceutically acceptable solventand an antitumor compound having a solubility in ethanol of at leastabout 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While not beingbound to a particular theory, it is believed that the ethanol solubilityof the antitumor compound may be directly related to its efficacy. Theantitumor compound can also be capable of being crystallized from asolution. In other words, a crystalline antitumor compound, such ascompound 1393, can be dissolved in a solvent to form a solution and thenrecrystallized upon evaporation of the solvent without the formation ofany amorphous antitumor compound. It is also preferred that theantitumor compound have an ID50 value (i.e, the drug concentrationproducing 50% inhibition of colony formation) of at least 4, 5, 6, 7, 8,9, or 10 times less that of paclitaxel when measured according to theprotocol set forth in the working examples.

Dosage form administration by these routes may be continuous orintermittent, depending, for example, upon the patient's physiologicalcondition, whether the purpose of the administration is therapeutic orprophylactic, and other factors known to and assessable by a skilledpractitioner.

Dosage and regimens for the administration of the pharmaceuticalcompositions of the invention can be readily determined by those withordinary skill in treating cancer. It is understood that the dosage ofthe antitumor compounds will be dependent upon the age, sex, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired. For any mode ofadministration, the actual amount of antitumor compound delivered, aswell as the dosing schedule necessary to achieve the advantageouseffects described herein, will also depend, in part, on such factors asthe bioavailability of the antitumor compound, the disorder beingtreated, the desired therapeutic dose, and other factors that will beapparent to those of skill in the art. The dose administered to ananimal, particularly a human, in the context of the present inventionshould be sufficient to effect the desired therapeutic response in theanimal over a reasonable period of time. Preferably, an effective amountof the antitumor compound, whether administered orally or by anotherroute, is any amount which would result in a desired therapeuticresponse when administered by that route. Preferably, the compositionsfor oral administration are prepared in such a way that a single dose inone or more oral preparations contains at least 20 mg of the antitumorcompound per m² of patient body surface area, or at least 50, 100, 150,200, 300, 400, or 500 mg of the antitumor compound per m² of patientbody surface area, wherein the average body surface area for a human is1.8 m². Preferably, a single dose of a composition for oraladministration contains from about 20 to about 600 mg of the antitumorcompound per m² of patient body surface area, more preferably from about25 to about 400 mg/m^(2,) even more preferably, from about 40 to about300 mg/m², and even more preferably from about 50 to about 200 mg/m².Preferably, the compositions for parenteral administration are preparedin such a way that a single dose contains at least 20 mg of theantitumor compound per m² of patient body surface area, or at least 40,50, 100, 150, 200, 300, 400, or 500 mg of the antitumor compound per m²of patient body surface area. Preferably, a single dose in one or moreparenteral preparations contains from about 20 to about 500 mg of theantitumor compound per m²of patient body surface area, more preferablyfrom about 40 to about 400 mg/m² and even more preferably, from about 60to about 350 mg/m². However, the dosage may vary depending on the dosingschedule which can be adjusted as necessary to achieve the desiredtherapeutic effect. It should be noted that the ranges of effectivedoses provided herein are not intended to limit the invention andrepresent preferred dose ranges. The most preferred dosage will betailored to the individual subject, as is understood and determinable byone of ordinary skill in the art without undue experimentation.

The concentration of the antitumor compound in a liquid pharmaceuticalcomposition is preferably between about 0.01 mg and about 10 mg per mlof the composition, more preferably between about 0.1 mg and about 7 mgper ml, even more preferably between about 0.5 mg and about 5 mg per ml,and most preferably between about 1.5 mg and about 4 mg per ml.Relatively low concentrations are generally preferred because theantitumor compound is most soluble in the solution at lowconcentrations. The concentration of the antitumor compound in a solidpharmaceutical composition for oral administration is preferably betweenabout 5 weight % and about 50 weight %, based on the total weight of thecomposition, more preferably between about 8 weight % and about 40weight %, and most preferably between about 10 weight % and about 30weight %.

In one embodiment, solutions for oral administration are prepared bydissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis a solution, such as Cremophor® EL solution, is added to the solutionwhile stirring to form a pharmaceutically acceptable solution for oraladministration to a patient. If desired, such solutions can beformulated to contain a minimal amount of, or to be free of, ethanol,which is known in the art to cause adverse physiological effects whenadministered at certain concentrations in oral formulations.

In another embodiment, powders or tablets for oral administration areprepared by dissolving an antitumor compound in any pharmaceuticallyacceptable solvent capable of dissolving the compound (e.g.,ethanol ormethylene chloride) to form a solution. The solvent can optionally becapable of evaporating when the solution is dried under vacuum. Anadditional carrier can be added to the solution prior to drying, such asCremophor® EL solution. The resulting solution is dried under vacuum toform a glass. The glass is then mixed with a binder to form a powder.The powder can be mixed with fillers or other conventional tablettingagents and processed to form a tablet for oral administration to apatient. The powder can also be added to any liquid carrier as describedabove to form a solution, emulsion, suspension or the like for oraladministration.

Emulsions for parenteral administration can be prepared by dissolving anantitumor compound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is an emulsion, suchas Liposyn® II or Liposyn® III emulsion, is added to the solution whilestirring to form a pharmaceutically acceptable emulsion for parenteraladministration to a patient. If desired, such emulsions can beformulated to contain a minimal amount of, or to be free of, ethanol orCremophor® solution, which are known in the art to cause adversephysiological effects when administered at certain concentrations inparenteral formulations.

Solutions for parenteral administration can be prepared by dissolving anantitumor compound in any pharmaceutically acceptable solvent capable ofdissolving the compound (e.g., ethanol or methylene chloride) to form asolution. An appropriate volume of a carrier which is a solution, suchas Cremophor® solution, is added to the solution while stirring to forma pharmaceutically acceptable solution for parenteral administration toa patient. If desired, such solutions can be formulated to contain aminimal amount of, or to be free of, ethanol or Cremophor® solution,which are known in the art to cause adverse physiological effects whenadministered at certain concentrations in parenteral formulations.

If desired, the emulsions or solutions described above for oral orparenteral administration can be packaged in IV bags, vials or otherconventional containers in concentrated form and diluted with anypharmaceutically acceptable liquid, such as saline, to form anacceptable taxane concentration prior to use as is known in the art.

Definitions

The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

The “substituted hydrocarbyl” moieties described herein are hydrocarbylmoieties which are substituted with at least one atom other than carbon,including moieties in which a carbon chain atom is substituted with ahetero atom such as nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or a halogen atom. These substituents include halogen,heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, keto, acyl, acyloxy, nitro, amino, amido, nitro, cyano, thiol,ketals, acetals, esters and ethers.

The term “heteroatom” shall mean atoms other than carbon and hydrogen.

The “heterosubstituted methyl” moieties described herein are methylgroups in which the carbon atom is covalently bonded to at least oneheteroatom and optionally with hydrogen, the heteroatom being, forexample, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, orhalogen atom. The heteroatom may, in turn, be substituted with otheratoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy,hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol,ketals, acetals, esters or ether moiety.

The “heterosubstituted acetate” moieties described herein are acetategroups in which the carbon of the methyl group is covalently bonded toat least one heteroatom and optionally with hydrogen, the heteroatombeing, for example, a nitrogen, oxygen, silicon, phosphorous, boron,sulfur, or halogen atom. The heteroatom may, in turn, be substitutedwith other atoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy,aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido,thiol, ketals, acetals, esters or ether moiety.

Unless otherwise indicated, the alkyl groups described herein arepreferably lower alkyl containing from one to eight carbon atoms in theprincipal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include methyl, ethyl, propyl, isopropyl,butyl, hexyl and the like.

Unless otherwise indicated, the alkenyl groups described herein arepreferably lower alkenyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include ethenyl, propenyl, isopropenyl,butenyl, isobutenyl, hexenyl, and the like.

Unless otherwise indicated, the alkynyl groups described herein arepreferably lower alkynyl containing from two to eight carbon atoms inthe principal chain and up to 20 carbon atoms. They may be straight orbranched chain and include ethynyl, propynyl, butynyl, isobutynyl,hexynyl, and the like.

The terms “aryl” or “ar” as used herein alone or as part of anothergroup denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl or substituted naphthyl. Phenyl andsubstituted phenyl are the more preferred aryl.

The terms “halogen” or “halo” as used herein alone or as part of anothergroup refer to chlorine, bromine, fluorine, and iodine.

The terms “heterocyclo” or “heterocyclic” as used herein alone or aspart of another group denote optionally substituted, fully saturated orunsaturated, monocyclic or bicyclic, aromatic or nonaromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heterocyclo include heteroaromatics such as furyl,thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, orisoquinolinyl and the like. Exemplary substituents include one or moreof the following groups: hydrocarbyl, substituted hydrocarbyl, keto,hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy,aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals,esters and ethers.

The term “heteroaromatic” as used herein alone or as part of anothergroup denote optionally substituted aromatic groups having at least oneheteroatom in at least one ring, and preferably 5 or 6 atoms in eachring. The heteroaromatic group preferably has 1 or 2 oxygen atoms, 1 or2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring, and may bebonded to the remainder of the molecule through a carbon or heteroatom.Exemplary heteroaromatics include furyl, thienyl, pyridyl, oxazolyl,pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like. Exemplarysubstituents include one or more of the following groups: hydrocarbyl,substituted hydrocarbyl, keto, hydroxy, protected hydroxy, acyl,acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido, amino,nitro, cyano, thiol, ketals, acetals, esters and ethers.

The term “acyl,” as used herein alone or as part of another group,denotes the moiety formed by removal of the hydroxyl group from thegroup —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein R isR¹, R¹O—, R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstitutedhydrocarbyl, or heterocyclo, and R² is hydrogen, hydrocarbyl orsubstituted hydrocarbyl.

The term “acyloxy,” as used herein alone or as part of another group,denotes an acyl group as described above bonded through an oxygenlinkage (—O—), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.”

Unless otherwise indicated, the alkoxycarbonyloxy moieties describedherein comprise lower hydrocarbon or substituted hydrocarbon orsubstituted hydrocarbon moieties.

Unless otherwise indicated, the carbamoyloxy moieties described hereinare derivatives of carbamic acid in which one or both of the aminehydrogens is optionally replaced by a hydrocarbyl, substitutedhydrocarbyl or heterocyclo moiety.

The terms “hydroxyl protecting group” and “hydroxy protecting group” asused herein denote a group capable of protecting a free hydroxyl group(“protected hydroxyl”) which, subsequent to the reaction for whichprotection is employed, may be removed without disturbing the remainderof the molecule. A variety of protecting groups for the hydroxyl groupand the synthesis thereof may be found in “Protective Groups in OrganicSynthesis” by T. W. Greene, John Wiley and Sons, 1981, or Fieser &Fieser. Exemplary hydroxyl protecting groups include methoxymethyl,1-ethoxyethyl, benzyloxymethyl, (.beta.-trimethylsilylethoxy)methyl,tetrahydropyranyl, 2,2,2-trichloroethoxycarbonyl,t-butyl(diphenyl)silyl, trialkylsilyl, trichloromethoxycarbonyl and2,2,2-trichloroethoxymethyl.

As used herein, “Ac” means acetyl; “Bz” means benzoyl; “Et” means ethyl;“Me” means methyl; “Ph” means phenyl; “Pr” means propyl; “Bu” meansbutyl; “Am” means amyl; “cpro” means cyclopropyl; “iPr” means isopropyl;“tBu” and “t-Bu” means tert-butyl; “R” means lower alkyl unlessotherwise defined; “Py” means pyridine or pyridyl; “TES” meanstriethylsilyl; “TMS” means trimethylsilyl; “LAH” means lithium aluminumhydride; “10-DAB” means 10-desacetylbaccatin III”; “amine protectinggroup” includes, but is not limited to, carbamates, for example,2,2,2-trichloroethylcarbamate or tertbutylcarbamate; “protected hydroxy”means—OP wherein P is a hydroxy protecting group; “PhCO” meansphenylcarbonyl; “tBuOCO” and “Boc” mean tert-butoxycarbonyl; “tAmOCO”means tert-amyloxycarbonyl; “2-FuCO” means 2-furylcarbonyl; “2-ThCO”means 2-thienylcarbonyl; “2-PyCO” means 2-pyridylcarbonyl; “3-PyCO”means 3-pyridylcarbonyl; “4-PyCO” means 4-pyridylcarbonyl; “C₄H₇CO”means butenylcarbonyl; “tC₃H₅CO” means trans-propenylcarbonyl; “EtOCO”means ethoxycarbonyl; “ibueCO” means isobutenylcarbonyl; “iBuCO” meansisobutylcarbonyl; “iBuOCO” means isobutoxycarbonyl; “iPrOCO” meansisopropyloxycarbonyl; “nPrOCO” means n-propyloxycarbonyl; “nPrCO” meansn-propylcarbonyl; “ibue” means isobutenyl; “THF” means tetrahydrofuran;“DMAP” means 4-dimethylamino pyridine; “LHMDS” means LithiumHexamethylDiSilazanide.

The following examples illustrate the invention.

EXAMPLE 1

10-Triethylsilyl-10deacetyl baccatin III. To a solution of 1.0 g (1.84mmol) of 10-deacetyl baccatin III in 50 mL of THF at −10° C. under anitrogen atmosphere was added 0.857 mL (2.76 mmol, 1.5 mol equiv) ofN,O-(bis)-TES-trifluoroacetamide over a period of 3 min. This wasfollowed by the addition of 0.062 mL of a 0.89 M THF solution of lithiumbis(trimethylsilyl)amide (0.055 mmol, 0.03 mol equiv). After 10 min0.038 mL (0.92 mmol, 0.5 mol equiv) of methanol was added, and after anadditional 5 min 4 mL (0.055 mmol, 0.03 mol equiv) of acetic acid wasadded. The solution was diluted with 300 mL of ethyl acetate and washedtwo times with 100 mL of saturated aqueous sodium bicarbonate solution.The combined aqueous layers were extracted with 100 mL of ethyl acetate(and the combined organic layers were washed with brine, dried oversodium sulfate, and concentrated under reduced pressure. To the residuewas added 100 mL of hexane and the solid (1.23 g, 101%) was collected byfiltration. Recrystallization of the solid by dissolving in boilingethyl acetate (20 mL, 17 mL/g) and cooling to room temperature gave1.132 g (94%) of a white solid. m.p. 242° C.; [α]_(D) ²⁵−60.4 (c 0.7,CHCl₃); ¹H NMR (CDCl₃, 400 MHz) δ(p.p.m): 8.10 (2H d, Jm=7.5 Hz, Bzo),7.60 (1H, t, Jm=7.5 Hz, Bzp), 7.47 (2H, t, Jo=7.5 Hz, Bzm), 5.64 (1H, d,J3=6.9 Hz, H2), 5.26 (1H, s, H10), 4.97 (1H, dd, J6β=2.2 Hz, J6α=9.9 Hz,H5), 4.85 (1H, dd, J14α=8.9 Hz, J14β=8.9 Hz, H13), 4.30 (1H, d, J20α=8.5Hz, H20α), 4.23 (1H, ddd, J7OH=4.5 Hz, J6α=6.6 Hz, J6β=11.0 Hz H7), 4.15(1H, d, J20α=8.5 Hz, H20β), 4.00 (1H, d, J2=6.9 Hz, H3), 2.58 (1H, ddd,J7=6.6 Hz, J5=9.9 Hz, J6β=14.5 Hz, H6α), 2.28-2.25 (5H, m, 4Ac, H14α,H14β), 2.02 (3H, s, 18Me), 1.97 (1H, d, J7=4.5 Hz, H7OH), 1.78 (1H, ddd,J7=11.0 Hz, J5=2.2 Hz, J6α=14.5 Hz, H6β), 1.68 (3H, s, 19Me), 1.56 (1H,s, OH1), 1.32 (1H, d, J13=8.8 Hz, OH13 ), 1.18 (3H, s, 17Me), 1.06 (3H,s, 16Me), 0.98 (9H, t, JCH₂(TES)=7.3 Hz, CH₃(TES)), 0.65 (6H, dq,JCH₃(TES)=7.3 Hz, CH₂(TES)).

10-Triethylsilyl-10-deacetyl-7-propionyl baccatin III. To a solution of1.0 g (1.517 mmol) of 10-triethylsilyl-10-deacetyl baccatin III and 37.0mg (0.303 mmol) of DMAP in 20 mL of dichloromethane at room temperatureunder a nitrogen atmosphere was added 0.920 mL (11.381 mmol) of pyridineand 0.329 mL (3.794 mmol, 2.5 mol equiv) of propionyl chloride in thatorder. The mixture was stirred at room temperature for 6 h, diluted with350 mL of ethyl acetate and extracted with 50 mL of 10% aqueous coppersulfate solution. The organic layer was washed with 50 mL of saturatedaqueous sodium bicarbonate solution, 50 mL of brine, dried over sodiumsulfate and concentrated under reduced pressure. The crude product wasdissolved in 75 mL of ethyl acetate, 100 mg of Norit A was added, themixture was filtered through celite and concentrated under reducedpressure to give 1.13 g of material. Recrystallization from ethylacetate/hexanes (dissolved in 6.5 mL of refluxing ethyl acetate, then 24mL of hexanes added, allowed to cool to room temperature, and left tostand for 17 h) afforded 787 mg (72.5%) of a white crystalline solid. Asecond recrystallization (ca 340 mg material dissolved in 2 mL ofrefluxing ethyl acetate, then 10 mL of hexanes added, allowed to cool toroom temperature, and allowed to stand for 17 h) afforded 181 mg (16.7%)of a white crystalline solid. The combined yield after recrystallizationwas 89.2%. m.p. 129° C.; [α]_(D) ²⁵−47.9 (c 1.0, CHCl₃); NMR ¹H (CDCl₃,300 MHz) δ(ppm): 8.10 (2H, d, Jm=7.4 Hz, Bzo), 7.60 (1H, t, Jm=7.4 Hz,Bzp), 7.48 (2H, dd, Jo=7.4 Hz, Jp=7.4 Hz, Bzm), 5.64 (1H, d, J3=7.4 Hz,H2), 5.47 (1H, dd, J6α=7.4 Hz, J6β=10.1 Hz, H7), 5.28 (1H, s, H10), 4.94(1H, d, J6α=9.4 Hz, H5), 4.80-4.90 (1H, m, H13), 4.31 (1H, d, J20β=8.1Hz, H20α), 4.16 (1H, J20α=8.1 Hz, H20β), 4.06 (1H, d, J2=7.4 Hz, H3),2.55 (1H, ddd, J7=7.4 Hz, J5 =9.4 Hz, J6α14.8 Hz, H6α), 2.28 (3H, s,4Ac), 2.23-2.32 (4H, m, 7CH₂, H14α, H14β), 2.07 (3H, s, 18Me), 2.02 (1H,d, J13=4.7 Hz, OH13), 1.76-1.87 (4H, m, H6β, 19Me), 1.60 (1H, s, OH1),1.17 (3H, s, 17Me), 1.09 (3H, t, J7CH₂=7.4 Hz, 7CH₃), 1.04 (3H, s,16Me), 0.96 (9H, t, JCH₂(TES)=8.0 Hz, CH₃(TES)), 0.52-0.62 (6H, m,CH₂(TES)).

2′-O-MOP-3′-desphenyl-3′-(2-furyl)-10-triethylsilyl-7-propionyltaxotere. To a solution of 493 mg (0.690 mmol) of10-triethylsilyl-10-deacetyl-7-propionyl baccatin III in 4 mL ofanhydrous THF under a nitrogen atmosphere at −45° C. was added 0.72 mL(0.72 mmol) of a 1M solution of LiHMDS in THF. After 0.5 h a solution of263 mg (0.814 mmol) of the b-Lactam (predried as described above) in 2mL of anhydrous THF was added. The mixture was warmed to 0° C., andafter 2 h 0.5 mL of saturated aqueous sodium bicarbonate solution wasadded. The mixture was diluted with 50 ml of ethyl acetate and washedtwo times with 5 mL of brine. The organic phase was dried over sodiumsulfate and concentrated under reduced pressure to give 742 mg (104%) ofa slightly yellow solid. The solid was recrystallized by dissolving itin 12 mL of a 1:5 mixture of ethyl acetate and hexane at reflux and thencooling to room temperature to give 627 mg (88%) of a white crystallinesolid. Evaporation of the mother liquor gave 96 mg of material which wasrecrystallized as above from 2 mL of a 1:5 mixture of ethyl acetate andhexane to give an additional 46 mg (6%) of white crystalline solid. Thetotal yield from recrystallization was 94%. Evaporation of the motherliquor gave 46 mg of material which was purified by columnchromatography on silica gel to give an additional 20 mg (3%) ofproduct. m.p. 207-209° C.; [α]_(D) ²⁵−30.0 (c 5.0, methanol); ¹H NMR(CDCl₃, 400 MHz) d (ppm): 8.09-8.11 (m, 2H), 7.58-7.61 (m, 1H),7.47-7.51(m, 2H), 7.39 (d, J=0.8 Hz, 1H), 6.34 (dd, J=3.2, 1.6 Hz, 1H),6.26 (d, J=3.2 Hz), 6.14 (dd, J=8.8, 8.8 Hz, 1H), 5.71 (d, J=6.8 Hz,1H), 5.47 (dd, J=10.0, 7.2 Hz, 1H), 5.30-5.36 (m, 2H), 5.28 (s, 1H),4.95 (d, J=7.6 Hz, 1H), 4.76 (s, 1H), 4.33 (d, J=8.0 Hz, 1H), 4,19 (d,J=8.4 Hz, 1H), 4.03 (d, J=6.8 Hz, 1H), 2.83 (s, 3H), 2.55 (ddd, J=17.2,9.6, 7.6, 1H), 2.50 (s, 3H), 2.20-2.40 (m, 2H), 2.28 (q, J=7.6 Hz, 2H),1.95 (s, 3H), 1.84 (ddd, J=14.8, 10.8, 2 Hz), 1.80 (s, 3H), 1.67 (s,1H), 1.39 (s, 9H), 1.32 (s, 3H), 1.21 (s, 3H), 1.20 (s, 3H), 1.74 (s,3H), 1.09 (t, J=7.6 Hz, 3H), 0.93-0.99 (m, 9H), 0.50-0.65 (m, 6H).

3′-Desphenyl-3′-(2-furyl)-7-propionyl taxotere. (1393) To a solution of206 mg (0.199 mmol) of2′-O-MOP-3′-desphenyl-3′-(2-furyl)-10-triethylsilyl-7-propionyltaxotere, in 1.7 mL of pyridine and 5.4 mL of acetonitrile at 0° C. wasadded 0.80 mL (2.0 mmol) of an aqueous solution containing 49% HF. Themixture was warmed to room temperature for 14 h and was then dilutedwith 20 mL of ethyl acetate and washed three times with 2 mL ofsaturated aqueous sodium bicarbonate and then with 8 mL of brine. Theorganic phase was dried over sodium sulfate and concentrated underreduced pressure to give 170 mg (100%) of a white solid. The crudeproduct was crystallized with 2 mL of solvent (CH₂Cl₂:hexane=1:1.7) togive 155 mg (90.5%) of white crystals. Concentration of the motherliquor under reduced pressure gave 15 mg of material which wasrecrystallized using 0.2 mL of a 1:1.7 mixture of methylene chloride andhexane to give an additional 11 mg (7.5%) of white crystals. The totalyield from recrystallization was 98%. m.p. 150-152° C.; [a]_(D) ²⁵−27.0(c 5.0, methanol); Anal. Calcd for C₄₄H₅₅NO₁₆.0.5H₂O: C, 61.18; H, 6.48.Found: C, 61.40; H, 6.65. ¹H NMR (CDCl₃, 500 MHz) d (ppm): 8.11 (d,J=7.5 Hz, 2H), 7.61 (dd, J=7.5, 7.5 Hz, 1H), 7.50 (dd, J=8.0, 7.5 Hz2H), 7.41 (d, J=1.0 Hz, 1H), 6.38 (dd, J=3.0, 2.0 Hz, 1H), 6.33 (d,J=3.5 Hz), 6.22 (dd, J=9.5, 9.5 Hz,1H), 5.69 (d, J=7.0 Hz, 1H), 5.49(dd, J=11.0, 7.5 Hz, 1H), 5.35 (d, J=9.5 Hz, 1H), 5.33 (d, J=1.5 Hz,1H),5.25 (d, J=9.5 Hz, 1H), 4.94 (d, J=8.5 Hz, 1H), 4.71 (dd, J=5.5, 2.0 Hz,1H), 4.33 (d, J=8.5 Hz, 1H), 4,21 (d, J=8.5 Hz, 1H), 4.01 (d, J=6.5 Hz,1H), 3.97 (d, J=1.5 Hz, 1H), 3.30 (d, J=5.5 Hz, 1H), 2.54 (ddd, J=16.5,9.5, 7.0, 1H), 2.41 (s, 3H), 2.37 (dd, J=15.0, 9.0 Hz, 1H), 2.30 (dd,J=17.5, 9.5 Hz, 1H), 2.25 (q, J=7.5 Hz, 2H), 1.96 (s, 3H), 1.93 (ddd,J=14.5, 11.0, 2.5 Hz), 1.85 (s, 3H), 1.64 (s, 1H), 1.36 (s, 9H), 1.23(s, 3H), 1.10 (t, J=7.5 Hz, 3H).

EXAMPLE 2

The procedures described in Example 1 were repeated, but other suitablyprotected β-lactams were substituted for the β-lactam of Example 1 toprepare the series of compounds having structural formula (13) and thecombinations of substituents identified in the following table.

(13)

Compound X₅ X₃ R₇ 1351 tBuOCO— ibue EtCOO— 1364 tBuOCO— 2-pyridyl EtCOO—1372 tBuOCO— 3-pyridyl EtCOO— 1386 tBuOCO— 4-pyridyl EtCOO— 1393 tBuOCO—2-furyl EtCOO— 1401 tBuOCO— 3-furyl EtCOO— 1418 tBuOCO— 2-thienyl EtCOO—1424 tBuOCO— 3-thienyl EtCOO— 1434 tBuOCO— isopropyl EtCOO— 1447 tBuOCO—cyclobutyl EtCOO— 1458 tBuOCO— phenyl EtCOO— 3069 2-FuCO— 2-thienylEtCOO— 3082 iPrOCO— 2-thienyl EtCOO— 3171 nPrCO— 2-furyl EtCOO— 3196iBuOCO— 2-furyl EtCOO— 3232 iBuOCO— 2-thienyl EtCOO— 3327 nPrCO—2-thienyl EtCOO— 3388 PhCO— 3-thienyl EtCOO— 3444 iPrOCO— 2-furyl EtCOO—3479 2-ThCO— 2-thienyl EtCOO— 3555 C₄H₇CO— 2-thienyl EtCOO— 3560tC₃H₅CO— 2-thienyl EtCOO— 3611 EtOCO— 2-furyl EtCOO— 3629 2-FuCO—2-furyl EtCOO— 3632 2-ThCO— 2-furyl EtCOO— 3708 tC₃H₅CO— 2-furyl EtCOO—3713 C₄H₇CO— 2-furyl EtCOO— 4017 PhCO— 2-furyl EtCOO— 4044 EtOCO—2-thienyl EtCOO— 4106 3-PyCO— 2-thienyl EtCOO— 4135 IPrOCO— 2-thienylPrCOO— 4175 PhCO— 2-thienyl PrCOO— 4219 2-FuCO— 2-thienyl PrCOO— 4256tBuOCO— 2-thienyl PrCOO— 4283 ibueCO— 2-thienyl PrCOO— 4290 iBuOCO—2-thienyl PrCOO— 4312 ibueCO— 2-thienyl EtCOO— 4388 2-ThCO— 2-thienylPrCOO— 4394 tBuOCO— 3-furyl PrCOO— 4406 tBuOCO— isobutenyl PrCOO— 4446tBuOCO— 3-thienyl PrCOO— 4499 tBuOCO— 2-furyl PrCOO— 4544 iBuOCO—3-thienyl EtCOO— 4600 iBuOCO— 3-thienyl PrCOO— 4616 iBuOCO— 2-furylPrCOO— 4737 tC₃H₅CO— 2-furyl PrCOO— 4757 tC₃H₅CO— 2-thienyl PrCOO— 6171ibueOCO— 2-furyl EtCOO— 6131 ibueOCO— 2-furyl iBuCOO— 5989 ibueOCO—2-furyl iPrCOO— 6141 ibueOCO— 2-furyl nBuCOO— 6181 ibueOCO— 2-furylnPrCOO— 6040 iBueOCO— 2-furyl ibueCOO— 6121 iPrCO— 2-furyl iPrCOO— 6424tAmOCO— 2-furyl EtCOO— 6212 tAmOCO— 2-furyl EtCOO— 6282 tAmOCO— 2-furyliBuCOO— 6252 tAmOCO— 2-furyl iPrCOO— 6343 tAmOCO— 2-furyl nBuCOO— 6272tAmOCO— 2-furyl nPrCOO— 6202 tC₃H₅CO— 2-furyl iPrCOO— 4454 2-ThCO—2-thienyl nPrCOO— 4414 PhCO— 2-thienyl nPrCOO— 6333 tBuOCO— 2-thienyliPrCOO— 6686 tBuOCO— 2-thienyl tC₃H₅COO— 6363 tBuOCO— 2-thiazo EtCOO—4787 iBuOCO— 3-furyl EtCOO— 4828 iBuOCO— 3-furyl nPrCOO— 4898 tC₃H₅CO—3-furyl EtCOO— 4939 tC₃H₅CO— 3-furyl nPrCOO— 5020 tC₃H₅CO— 3-thienylEtCOO— 5030 tC₃H₅CO— 3-thienyl nPrCOO— 5191 iBuOCO— cpro EtCOO— 5202iBuOCO— cpro nPrCOO— 5070 tBuOCO— cpro EtCOO— 5080 tBuOCO— cpro nPrCOO—5121 iBuOCO— ibue EtCOO— 5131 iBuOCO— ibue nPrCOO—

EXAMPLE 3

Following the processes described in Example 1 and elsewhere herein, thefollowing specific taxanes having structural formula 14 may be prepared,wherein R₇ is as previously defined, including wherein R₇ is R_(7a)COO—and R_(7a) is (i) substituted or unsubstituted C₂ to C₈ alkyl (straight,branched or cyclic), such as ethyl, propyl, butyl, pentyl, or hexyl;(ii) substituted or unsubstituted C₂ to C₈ alkenyl (straight, branchedor cyclic), such as ethenyl, propenyl, butenyl, pentenyl or hexenyl;(iii) substituted or unsubstituted C₂ to C₈ alkynyl (straight orbranched) such as ethynyl, propynyl, butynyl, pentynyl, or hexynyl; (iv)substituted or unsubstituted phenyl; or (v) substituted or unsubstitutedheterocyclo such as furyl, thienyl, or pyridyl. The substituents may behydrocarbyl or any of the heteroatom containing substituents selectedfrom the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy,aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido,thiol, ketal, acetal, ester and ether moieties, but not phosphorouscontaining moieties.

(14)

X₅ X₃ R₇ tBuOCO— 2-furyl R_(a)COO— tBuOCO— 3-furyl R_(a)COO— tBuOCO—2-thienyl R_(a)COO— tBuOCO— 3-thienyl R_(a)COO— tBuOCO— 2-pyridylR_(a)COO— tBuOCO— 3-pyridyl R_(a)COO— tBuOCO— 4-pyridyl R_(a)COO—tBuOCO— isobutenyl R_(a)COO— tBuOCO— isopropyl R_(a)COO— tBuOCO—cyclopropyl R_(a)COO— tBuOCO— cyclobutyl R_(a)COO— tBuOCO— cyclopentylR_(a)COO— tBuOCO— phenyl R_(a)COO— benzoyl 2-furyl R_(a)COO— benzoyl3-furyl R_(a)COO— benzoyl 2-thienyl R_(a)COO— benzoyl 3-thienylR_(a)COO— benzoyl 2-pyridyl R_(a)COO— benzoyl 3-pyridyl R_(a)COO—benzoyl 4-pyridyl R_(a)COO— benzoyl isobutenyl R_(a)COO— benzoylisopropyl R_(a)COO— benzoyl cyclopropyl R_(a)COO— benzoyl cyclobutylR_(a)COO— benzoyl cyclopentyl R_(a)COO— benzoyl phenyl R_(a)COO— 2-FuCO—2-furyl R_(a)COO— 2-FuCO— 3-furyl R_(a)COO— 2-FuCO— 2-thienyl R_(a)COO—2-FuCO— 3-thienyl R_(a)COO— 2-FuCO— 2-pyridyl R_(a)COO— 2-FuCO—3-pyridyl R_(a)COO— 2-FuCO— 4-pyridyl R_(a)COO— 2-FuCO— isobutenylR_(a)COO— 2-FuCO— isopropyl R_(a)COO— 2-FuCO— cyclopropyl R_(a)COO—2-FuCO— cyclobutyl R_(a)COO— 2-FuCO— cyclopentyl R_(a)COO— 2-FuCO—phenyl R_(a)COO— 2-ThCO- 2-furyl R_(a)COO— 2-ThCO— 3-furyl R_(a)COO—2-ThCO— 2-thienyl R_(a)COO— 2-ThCO— 3-thienyl R_(a)COO— 2-ThCO—2-pyridyl R_(a)COO— 2-ThCO— 3-pyridyl R_(a)COO— 2-ThCO— 4-pyridylR_(a)COO— 2-ThCO— isobutenyl R_(a)COO— 2-ThCO— isopropyl R_(a)COO—2-ThCO— cyclopropyl R_(a)COO— 2-ThCO— cyclobutyl R_(a)COO— 2-ThCO—cyclopentyl R_(a)COO— 2-ThCO— phenyl R_(a)COO— 2-PyCO— 2-furyl R_(a)COO—2-PyCO— 3-furyl R_(a)COO— 2-PyCO— 2-thienyl R_(a)COO— 2-PyCO— 3-thienylR_(a)COO— 2-PyCO— 2-pyridyl R_(a)COO— 2-PyCO— 3-pyridyl R_(a)COO—2-PyCO— 4-pyridyl R_(a)COO— 2-PyCO— isobutenyl R_(a)COO— 2-PyCO—isopropyl R_(a)COO— 2-PyCO— cyclopropyl R_(a)COO— 2-PyCO— cyclobutylR_(a)COO— 2-PyCO— cyclopentyl R_(a)COO— 2-PyCO— phenyl R_(a)COO— 3-PyCO—2-furyl R_(a)COO— 3-PyCO— 3-furyl R_(a)COO— 3-PyCO— 2-thienyl R_(a)COO—3-PyCO— 3-thienyl R_(a)COO— 3-PyCO— 2-pyridyl R_(a)COO— 3-PyCO—3-pyridyl R_(a)COO— 3-PyCO— 4-pyridyl R_(a)COO— 3-PyCO— isobutenylR_(a)COO— 3-PyCO— isopropyl R_(a)COO— 3-PyCO— cyclopropyl R_(a)COO—3-PyCO— cyclobutyl R_(a)COO— 3-PyCO— cyclopentyl R_(a)COO— 3-PyCO—phenyl R_(a)COO— 4-PyCO— 2-furyl R_(a)COO— 4-PyCO— 3-furyl R_(a)COO—4-PyCO— 2-thienyl R_(a)COO— 4-PyCO— 3-thienyl R_(a)COO— 4-PyCO—2-pyridyl R_(a)COO— 4-PyCO— 3-pyridyl R_(a)COO— 4-PyCO— 4-pyridylR_(a)COO— 4-PyCO— isobutenyl R_(a)COO— 4-PyCO— isopropyl R_(a)COO—4-PyCO— cyclopropyl R_(a)COO— 4-PyCO— cyclobutyl R_(a)COO— 4-PyCO—cyclopentyl R_(a)COO— 4-PyCO— phenyl R_(a)COO— C₄H₇CO— 2-furyl R_(a)COO—C₄H₇CO— 3-furyl R_(a)COO— C₄H₇CO— 2-thienyl R_(a)COO— C₄H₇CO— 3-thienylR_(a)COO— C₄H₇CO— 2-pyridyl R_(a)COO— C₄H₇CO— 3-pyridyl R_(a)COO—C₄H₇CO— 4-pyridyl R_(a)COO— C₄H₇CO— isobutenyl R_(a)COO— C₄H₇CO—isopropyl R_(a)COO— C₄H₇CO— cyclopropyl R_(a)COO— C₄H₇CO— cyclobutylR_(a)COO— C₄H₇CO— cyclopentyl R_(a)COO— C₄H₇CO— phenyl R_(a)COO— EtOCO—2-furyl R_(a)COO— EtOCO— 3-furyl R_(a)COO— EtOCO— 2-thienyl R_(a)COO—EtOCO— 3-thienyl R_(a)COO— EtOCO— 2-pyridyl R_(a)COO— EtOCO— 3-pyridylR_(a)COO— EtOCO— 4-pyridyl R_(a)COO— EtOCO— isobutenyl R_(a)COO— EtOCO—isopropyl R_(a)COO— EtOCO— cyclopropyl R_(a)COO— EtOCO— cyclobutylR_(a)COO— EtOCO— cyclopentyl R_(a)COO— EtOCO— phenyl R_(a)COO— ibueCO—2-furyl R_(a)COO— ibueCO— 3-furyl R_(a)COO— ibueCO— 2-thienyl R_(a)COO—ibueCO— 3-thienyl R_(a)COO— ibueCO— 2-pyridyl R_(a)COO— ibueCO—3-pyridyl R_(a)COO— ibueCO— 4-pyridyl R_(a)COO— ibueCO— isobutenylR_(a)COO— ibueCO— isopropyl R_(a)COO— ibueCO— cyclopropyl R_(a)COO—ibueCO— cyclobutyl R_(a)COO— ibueCO— cyclopentyl R_(a)COO— ibueCO—phenyl R_(a)COO— iBuCO— 2-furyl R_(a)COO— iBuCO— 3-furyl R_(a)COO—iBuCO— 2-thienyl R_(a)COO— iBuCO— 3-thienyl R_(a)COO— iBuCO— 2-pyridylR_(a)COO— iBuCO— 3-pyridyl R_(a)COO— iBuCO— 4-pyridyl R_(a)COO— iBuCO—isobutenyl R_(a)COO— iBuCO— isopropyl R_(a)COO— iBuCO— cyclopropylR_(a)COO— iBuCO— cyclobutyl R_(a)COO— iBuCO— cyclopentyl R_(a)COO—iBuCO— phenyl R_(a)COO— iBuOCO— 2-furyl R_(a)COO— iBuOCO— 3-furylR_(a)COO— iBuOCO— 2-thienyl R_(a)COO— iBuOCO— 3-thienyl R_(a)COO—iBuOCO— 2-pyridyl R_(a)COO— iBuOCO— 3-pyridyl R_(a)COO— iBuOCO—4-pyridyl R_(a)COO— iBuOCO— isobutenyl R_(a)COO— iBuOCO— isopropylR_(a)COO— iBuOCO— cyclopropyl R_(a)COO— iBuOCO— cyclobutyl R_(a)COO—iBuOCO— cyclopentyl R_(a)COO— iBuOCO— phenyl R_(a)COO— iPrOCO— 2-furylR_(a)COO— iPrOCO— 3-furyl R_(a)COO— iPrOCO— 2-thienyl R_(a)COO— iPrOCO—3-thienyl R_(a)COO— iPrOCO— 2-pyridyl R_(a)COO— iPrOCO— 3-pyridylR_(a)COO— iPrOCO— 4-pyridyl R_(a)COO— iPrOCO— isobutenyl R_(a)COO—iPrOCO— isopropyl R_(a)COO— iPrOCO— cyclopropyl R_(a)COO— iPrOCO—cyclobutyl R_(a)COO— iPrOCO— cyclopentyl R_(a)COO— iPrOCO— phenylR_(a)COO— nPrOCO— 2-furyl R_(a)COO— nPrOCO— 3-furyl R_(a)COO— nPrOCO—2-thienyl R_(a)COO— nPrOCO— 3-thienyl R_(a)COO— nPrOCO— 2-pyridylR_(a)COO— nPrOCO— 3-pyridyl R_(a)COO— nPrOCO— 4-pyridyl R_(a)COO—nPrOCO— isobutenyl R_(a)COO— nPrOCO— isopropyl R_(a)COO— nPrOCO—cyclopropyl R_(a)COO— nPrOCO— cyclobutyl R_(a)COO— nPrOCO— cyclopentylR_(a)COO— nPrOCO— phenyl R_(a)COO— nPrCO— 2-furyl R_(a)COO— nPrCO—3-furyl R_(a)COO— nPrCO— 2-thienyl R_(a)COO— nPrCO— 3-thienyl R_(a)COO—nPrCO— 2-pyridyl R_(a)COO— nPrCO— 3-pyridyl R_(a)COO— nPrCO— 4-pyridylR_(a)COO— nPrCO— isobutenyl R_(a)COO— nPrCO— isopropyl R_(a)COO— nPrCO—cyclopropyl R_(a)COO— nPrCO— cyclobutyl R_(a)COO— nPrCO— cyclopentylR_(a)COO— nPrCO— phenyl R_(a)COO— tBuCOO— cyclopentyl EtCOO— benzoyl3-furyl EtCOO— benzoyl 2-thienyl EtCOO— benzoyl 2-pyridyl EtCOO— benzoyl3-pyridyl EtCOO— benzoyl 4-pyridyl EtCOO— benzoyl isobutenyl EtCOO—benzoyl isopropyl EtCOO— benzoyl cyclopropyl EtCOO— benzoyl cyclobutylEtCOO— benzoyl cyclopentyl EtCOO— benzoyl phenyl EtCOO— 2-FuCO— 3-furylEtCOO— 2-FuCO— 3-thienyl EtCOO— 2-FuCO— 2-pyridyl EtCOO— 2-FuCO—3-pyridyl EtCOO— 2-FuCO— 4-pyridyl EtCOO— 2-FuCO— isobutenyl EtCOO—2-FuCO— isopropyl EtCOO— 2-FuCO— cyclopropyl EtCOO— 2-FuCO— cyclobutylEtCOO— 2-FuCO— cyclopentyl EtCOO— 2-FuCO— phenyl EtCOO— 2-ThCO— 3-furylEtCOO— 2-ThCO— 3-thienyl EtCOO— 2-ThCO— 2-pyridyl EtCOO— 2-ThCO—3-pyridyl EtCOO— 2-ThCO— 4-pyridyl EtCOO— 2-ThCO— isobutenyl EtCOO—2-ThCO— isopropyl EtCOO— 2-ThCO— cyclopropyl EtCOO— 2-ThCO— cyclobutylEtCOO— 2-ThCO— cyclopentyl EtCOO— 2-ThCO— phenyl EtCOO— 2-PyCO— 2-furylEtCOO— 2-PyCO— 3-furyl EtCOO— 2-PyCO— 2-thienyl EtCOO— 2-PyCO— 3-thienylEtCOO— 2-PyCO— 2-pyridyl EtCOO— 2-PyCO— 3-pyridyl EtCOO— 2-PyCO—4-pyridyl EtCOO— 2-PyCO— isobutenyl EtCOO— 2-PyCO— isopropyl EtCOO—2-PyCO— cyclopropyl EtCOO— 2-PyCO— cyclobutyl EtCOO— 2-PyCO— cyclopentylEtCOO— 2-PyCO— phenyl EtCOO— 3-PyCO— 2-furyl EtCOO— 3-PyCO— 3-furylEtCOO— 3-PyCO— 3-thienyl EtCOO— 3-PyCO— 2-pyridyl EtCOO— 3-PyCO—3-pyridyl EtCOO— 3-PyCO— 4-pyridyl EtCOO— 3-PyCO— isobutenyl EtCOO—3-PyCO— isopropyl EtCOO— 3-PyCO— cyclopropyl EtCOO— 3-PyCO— cyclobutylEtCOO— 3-PyCO— cyclopentyl EtCOO— 3-PyCO— phenyl EtCOO— 4-PyCO— 2-furylEtCOO— 4-PyCO— 3-furyl EtCOO— 4-PyCO— 2-thienyl EtCOO— 4-PyCO— 3-thienylEtCOO— 4-PyCO— 2-pyridyl EtCOO— 4-PyCO— 3-pyridyl EtCOO— 4-PyCO—4-pyridyl EtCOO— 4-PyCO— isobutenyl EtCOO— 4-PyCO— isopropyl EtCOO—4-PyCO— cyclopropyl EtCOO— 4-PyCO— cyclobutyl EtCOO— 4-PyCO— cyclopentylEtCOO— 4-PyCO— phenyl EtCOO— 4-PyCO— 3-furyl EtCOO— 4-PyCO— 3-thienylEtCOO— C₄H₇CO— 2-pyridyl EtCOO— C₄H₇CO— 3-pyridyl EtCOO— C₄H₇CO—4-pyridyl EtCOO— C₄H₇CO— isobutenyl EtCOO— C₄H₇CO— isopropyl EtCOO—C₄H₇CO— cyclopropyl EtCOO— C₄H₇CO— cyclobutyl EtCOO— C₄H₇CO— cyclopentylEtCOO— C₄H₇CO— phenyl EtCOO— EtOCO— 3-furyl EtCOO— EtOCO— 3-thienylEtCOO— EtOCO— 2-pyridyl EtCOO— EtOCO— 3-pyridyl EtCOO— EtOCO— 4-pyridylEtCOO— EtOCO— isobutenyl EtCOO— EtOCO— isopropyl EtCOO— EtOCO—cyclopropyl EtCOO— EtOCO— cyclobutyl EtCOO— EtOCO— cyclopentyl EtCOO—EtOCO— phenyl EtCOO— ibueCO— 2-furyl EtCOO— ibueCO— 3-furyl EtCOO—ibueCO— 2-thienyl EtCOO— ibueCO— 3-thienyl EtCOO— ibueCO— 2-pyridylEtCOO— ibueCO— 3-pyridyl EtCOO— ibueCO— 4-pyridyl EtCOO— ibueCO—isobutenyl EtCOO— ibueCO— isopropyl EtCOO— ibueCO— cyclopropyl EtCOO—ibueCO— cyclobutyl EtCOO— ibueCO— cyclopentyl EtCOO— ibueCO— phenylEtCOO— iBuCO— 2-furyl EtCOO— iBuCO— 3-furyl EtCOO— iBuCO— 2-thienylEtCOO— iBuCO— 3-thienyl EtCOO— iBuCO— 2-pyridyl EtCOO— iBuCO— 3-pyridylEtCOO— iBuCO— 4-pyridyl EtCOO— iBuCO— isobutenyl EtCOO— iBuCO— isopropylEtCOO— iBuCO— cyclopropyl EtCOO— iBuCO— cyclobutyl EtCOO— iBuCO—cyclopentyl EtCOO— iBuCO— phenyl EtCOO— iBuOCO— 2-pyridyl EtCOO— iBuOCO—3-pyridyl EtCOO— iBuOCO— 4-pyridyl EtCOO— iBuOCO— isobutenyl EtCOO—iBuOCO— isopropyl EtCOO— iBuOCO— cyclobutyl EtCOO— iBuOCO— cyclopentylEtCOO— iBuOCO— phenyl EtCOO— iPrOCO— 3-furyl EtCOO— iPrOCO— 3-thienylEtCOO— iPrOCO— 2-pyridyl EtCOO— iPrOCO— 3-pyridyl EtCOO— iPrOCO—4-pyridyl EtCOO— iPrOCO— isobutenyl EtCOO— iPrOCO— isopropyl EtCOO—iPrOCO— cyclopropyl EtCOO— iPrOCO— cyclobutyl EtCOO— iPrOCO— cyclopentylEtCOO— iPrOCO— phenyl EtCOO— nPrOCO— 2-furyl EtCOO— nPrOCO— 3-furylEtCOO— nPrOCO— 2-thienyl EtCOO— nPrOCO— 3-thienyl EtCOO— nPrOCO—2-pyridyl EtCOO— nPrOCO— 3-pyridyl EtCOO— nPrOCO— 4-pyridyl EtCOO—nPrOCO— isobutenyl EtCOO— nPrOCO— isopropyl EtCOO— nPrOCO— cyclopropylEtCOO— nPrOCO— cyclobutyl EtCOO— nPrOCO— cyclopentyl EtCOO— nPrOCO—phenyl EtCOO— nPrCO— 3-furyl EtCOO— nPrCO— 3-thienyl EtCOO— nPrCO—2-pyridyl EtCOO— nPrCO— 3-pyridyl EtCOO— nPrCO— 4-pyridyl EtCOO— nPrCO—isobutenyl EtCOO— nPrCO— isopropyl EtCOO— nPrCO— cyclopropyl EtCOO—nPrCO— cyclobutyl EtCOO— nPrCO— cyclopentyl EtCOO— nPrCO— phenyl EtCOO—

EXAMPLE 4

Following the processes described in Example 1 and elsewhere herein, thefollowing specific taxanes having structural formula 15 may be prepared,wherein R₁₀ is hydroxy and R₇ in each of the series (that is, each ofseries “A” through “K”) is as previously defined, including wherein R₇is R_(7a)COO— and R₇a is (i) substituted or unsubstituted, preferablyunsubstituted, C₂ to C₈ alkyl (straight, branched or cyclic), such asethyl, propyl, butyl, pentyl, or hexyl; (ii) substituted orunsubstituted, preferably unsubstituted, C₂ to C₈ alkenyl (straight,branched or cyclic), such as ethenyl, propenyl, butenyl, pentenyl orhexenyl; (iii) substituted or unsubstituted, preferably unsubstituted,C₂ to C₈ alkynyl (straight or branched) such as ethynyl, propynyl,butynyl, pentynyl, or hexynyl; (iv) substituted or unsubstituted,preferably unsubstituted, phenyl; or (v) substituted or unsubstituted,preferably unsubstituted, heteroaromatic such as furyl, thienyl, orpyridyl.

In the “A” series of compounds, X₁₀ is as otherwise as defined herein.Preferably, heterocyclo is substituted or unsubstitued furyl, thienyl,or pyridyl, X₁₀ is substituted or unsubstitued furyl, thienyl, pyridyl,phenyl, or lower alkyl (e.g., tert-butyl), and R₇ and R₁₀ each have thebeta stereochemical configuration.

In the “B” series of compounds, X₁₀ and R_(2a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

In the “C” series of compounds, X₁₀ and R_(9a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R₉, is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “D” and “E” series of compounds, X₁₀ is as otherwise as definedherein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), and R₇, R₉ (series D only) and R₁₀ each have the betastereochemical configuration.

In the “F” series of compounds, X₁₀, R_(2a) and R_(9a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “G” series of compounds, X₁₀ and R_(2a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “H” series of compounds, X₁₀ is as otherwise as defined herein.Preferably, heterocyclo is preferably substituted or unsubstitued furyl,thienyl, or pyridyl, X₁₀ is preferably substituted or unsubstituedfuryl, thienyl, pyridyl, phenyl, or lower alkyl (e.g., tert-butyl),R_(2a) is preferably substituted or unsubstitued furyl, thienyl,pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have the betastereochemical configuration.

In the “I” series of compounds, X₁₀ and R_(2a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

In the “J” series of compounds, X₁₀ and R_(2a) are as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

In the “K” series of compounds, X₁₀, R_(2a) and R_(9a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

Any substituents of each X₃, X₅, R₂, R₇, and R₉ may be hydrocarbyl orany of the heteroatom containing substituents selected from the groupconsisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy,protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal,acetal, ester and ether moieties, but not phosphorous containingmoieties.

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Series X₅ X₃ R₇ R₂ R₉ R₁₄ A1 —COOX₁₀ heterocyclo R_(7a)COO— C₆H₅COO— O HA2 —COX₁₀ heterocyclo R_(7a)COO— C₆H₅COO— O H A3 —CONHX₁₀ heterocycloR_(7a)COO— C₆H₅COO— O H A4 —COOX₁₀ optionally R_(7a)COO— C₆H₅COO— O Hsubstituted C₂ to C₈ alkyl A5 —COX₁₀ optionally R_(7a)COO— C₆H₅COO— O Hsubstituted C₂ to C₈ alkyl A6 —CONHX₁₀ optionally R_(7a)COO— C₆H₅CCO— OH substituted C₂ to C₈ alkyl A7 —COOX₁₀ optionally R_(7a)COO— C₆H₅COO— OH substituted C₂ to C₈ alkenyl A8 —COX₁₀ optionally R_(7a)COO— C₆H₅COO—O H substituted C₂ to C₈ alkenyl A9 —CONHX₁₀ optionally R_(7a)COO—C₆H₅COO— O H substituted C₂ to C₈ alkenyl A10 —COOX₁₀ optionallyR_(7a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkynyl A11 —COX₁₀optionally R_(7a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkynyl A12—CONHX₁₀ optionally R_(7a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkynylB1 —COOX₁₀ heterocyclo R_(7a)COO— R_(2a)COO— O H B2 —COX₁₀ heterocycloR_(7a)COO— R_(2a)COO— O H B3 —CONHX₁₀ heterocyclo R_(7a)COO— R_(2a)COO—O H B4 —COOX₁₀ optionally R_(7a)COO— R_(2a)COO— O H substituted C₂ to C₈alkyl B5 —COX₁₀ optionally R_(7a)COO— R_(2a)COO— O H substituted C₂ toC₈ alkyl B6 —CONHX₁₀ optionally R_(7a)COO— R_(2a)COO— O H substituted C₂to C₈ alkyl B7 —COOX₁₀ optionally R_(7a)COO— R_(2a)COO— O H substitutedC₂ to C₈ alkenyl B8 —COX₁₀ optionally R_(7a)COO— R_(2a)COO— O Hsubstituted C₂ to C₈ alkenyl B9 —CONHX₁₀ optionally R_(7a)COO—R_(2a)COO— O H substituted C₂ to C₈ alkenyl B10 —COOX₁₀ optionallyR_(7a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkynyl B11 —COX₁₀optionally R_(7a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkynyl B12—CONHX₁₀ optionally R_(7a)COO— R_(2a)COO— O H substituted C₂ to C₈alkynyl C1 —COOX₁₀ heterocyclo R_(7a)COO— C₆H₅COO— R_(9a)COO— H C2—COX₁₀ heterocyclo R_(7a)COO— C₆H₅COO— R_(9a)COO— H C3 —CONHX₁₀heterocyclo R_(7a)COO— C₆H₅COO— R_(9a)COO— H C4 —COOX₁₀ optionallyR_(7a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkyl C5 —COX₁₀optionally R_(7a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkylC6 —CONHX₁₀ optionally R_(7a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂to C₈ alkyl C7 —COOX₁₀ optionally R_(7a)COO— C₆H₅COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl C8 —COX₁₀ optionally R_(7a)COO— C₆H₅COO—R_(9a)COO— H substituted C₂ to C₈ alkenyl C9 —CONHX₁₀ optionallyR_(7a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl C10—COOX₁₀ optionally R_(7a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈alkynyl C11 —COX₁₀ optionally R_(7a)COO— C₆H₅COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkynyl C12 —CONHX₁₀ optionally R_(7a)COO— C₆H₅COO—R_(9a)COO— H substituted C₂ to C₈ alkynyl D1 —COOX₁₀ heterocycloR_(7a)COO— C₆H₅COO— OH H D2 —COX₁₀ heterocyclo R_(7a)COO— C₆H₅COO— OH HD3 —CONHX₁₀ heterocyclo R_(7a)COO— C₆H₅COO— OH H D4 —COOX₁₀ optionallyR_(7a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D5 —COX₁₀ optionallyR_(7a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D6 —CONHX₁₀optionally R_(7a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D7—COOX₁₀ optionally R_(7a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkenylD8 —COX₁₀ optionally R_(7a)COO— C₆H₅COO— OH H substituted C₂ to C₈alkenyl D9 —CONHX₁₀ optionally R_(7a)COO— C₆H₅COO— OH H substituted C₂to C₈ alkenyl D10 —COOX₁₀ optionally R_(7a)COO— C₆H₅COO— OH Hsubstituted C₂ to C₈ alkynyl D11 —COX₁₀ optionally R_(7a)COO— C₆H₅COO—OH H substituted C₂ to C₈ alkynyl D12 —CONHX₁₀ optionally R_(7a)COO—C₆H₅COO— OH H substituted C₂ to C₈ alkynyl E1 —COOX₁₀ heterocycloR_(7a)COO— C₆H₅COO— O OH E2 —COX₁₀ heterocyclo R_(7a)COO— C₆H₅COO— O OHE3 —CONHX₁₀ heterocyclo R_(7a)COO— C₆H₅COO— O OH E4 —COOX₁₀ optionallyR_(7a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkyl E5 —COX₁₀ optionallyR_(7a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkyl E6 —CONHX₁₀optionally R_(7a)COO— C₆H₈COO— O OH substituted C₂ to C₈ alkyl E7—COOX₁₀ optionally R_(7a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkenylE8 —COX₁₀ optionally R_(7a)COO— C₆H₅COO— O OH substituted C₂ to C₈alkenyl E9 —CONHX₁₀ optionally R_(7a)COO— C₆H₅COO— O OH substituted C₂to C₈ alkenyl E10 —COOX₁₀ optionally R_(7a)COO— C₆H₅COO— O OHsubstituted C₂ to C₈ alkynyl E11 —COX₁₀ optionally R_(7a)COO— C₆H₅COO— OOH substituted C₂ to C₈ alkynyl E12 —CONHX₁₀ optionally R_(7a)COO—C₆H₅COO— O OH substituted C₂ to C₈ alkynyl F1 —COOX₁₀ heterocycloR_(7a)COO— R_(2a)COO— R_(9a)COO— H F2 —COX₁₀ heterocyclo R_(7a)COO—R_(2a)COO— R_(9a)COO— H F3 —CONHX₁₀ heterocyclo R_(7a)COO— R_(2a)COO—R_(9a)COO— H F4 —COOX₁₀ optionally R_(7a)COO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkyl F5 —COX₁₀ optionally R_(7a)COO— R_(2a)COO—R_(9a)COO— H substituted C₂ to C₈ alkyl F6 —CONHX₁₀ optionallyR_(7a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkyl F7 —COOX₁₀optionally R_(7a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈alkenyl F8 —COX₁₀ optionally R_(7a)COO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl F9 —CONHX₁₀ optionally R_(7a)COO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl F10 —COOX₁₀optionally R_(7a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈alkynyl F11 —COX₁₀ optionally R_(7a)COO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkynyl F12 —CONHX₁₀ optionally R_(7a)COO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl G1 —COOX₁₀heterocyclo R_(7a)COO— R_(2a)COO— OH H G2 —COX₁₀ heterocyclo R_(7a)COO—R_(2a)COO— OH H G3 —CONHX₁₀ heterocyclo R_(7a)COO— R_(2a)COO— OH H G4—COOX₁₀ optionally R_(7a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkylG5 —COX₁₀ optionally R_(7a)COO— R_(2a)COO— OH H substituted C₂ to C₈alkyl G6 —CONHX₁₀ optionally R_(7a)COO— R_(2a)COO— OH H substituted C₂to C₈ alkyl G7 —COOX₁₀ optionally R_(7a)COO— R_(2a)COO— OH H substitutedC₂ to C₈ alkenyl G8 —COX₁₀ optionally R_(7a)COO— R_(2a)COO— OH Hsubstituted C₂ to C₈ alkenyl G9 —CONHX₁₀ optionally R_(7a)COO—R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G10 —COOX₁₀ optionallyR_(7a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkynyl G11 —COX₁₀optionally R_(7a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkynyl G12—CONHX₁₀ optionally R_(7a)COO— R_(2a)COO— OH H substituted C₂ to C₈alkynyl H1 —COOX₁₀ heterocyclo R_(7a)COO— C₆H₅COO— OH OH H2 —COX₁₀heterocyclo R_(7a)COO— C₆H₅COO— OH OH H3 —CONHX₁₀ heterocyclo R_(7a)COO—C₆H₅COO— OH OH H4 —COOX₁₀ optionally R_(7a)COO— C₆H₅COO— OH OHsubstituted C₂ to C₈ alkyl H5 —COX₁₀ optionally R_(7a)COO— C₆H₅COO— OHOH substituted C₂ to C₈ alkyl H6 —CONHX₁₀ optionally R_(7a)COO— C₆H₅COO—OH OH substituted C₂ to C₈ alkyl H7 —COOX₁₀ optionally R_(7a)COO—C₆H₅COO— OH OH substituted C₂ to C₈ alkenyl H8 —COX₁₀ optionallyR_(7a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkenyl H9 —CONHX₁₀optionally R_(7a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkenyl H10—COOX₁₀ optionally R_(7a)COO— C₆H₅COO— OH OH substituted C₂ to C₈alkynyl H11 —COX₁₀ optionally R_(7a)COO— C₆H₅COO— OH OH substituted C₂to C₈ alkynyl H12 —CONHX₁₀ optionally R_(7a)COO— C₆H₅COO— OH OHsubstituted C₂ to C₈ alkynyl I1 —COOX₁₀ heterocyclo R_(7a)COO—R_(2a)COO— O OH I2 —COX₁₀ heterocyclo R_(7a)COO— R_(2a)COO— O OH I3—CONHX₁₀ heterocyclo R_(7a)COO— R_(2a)COO— O OH I4 —COOX₁₀ optionallyR_(7a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkyl I5 —COX₁₀optionally R_(7a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkyl I6—CONHX₁₀ optionally R_(7a)COO— R_(2a)COO— O OH substituted C₂ to C₈alkyl I7 —COOX₁₀ optionally R_(7a)COO— R_(2a)COO— O OH substituted C₂ toC₈ alkenyl I8 —COX₁₀ optionally R_(7a)COO— R_(2a)COO— O OH substitutedC₂ to C₈ alkenyl I9 —CONHX₁₀ optionally R_(7a)COO— R_(2a)COO— O OHsubstituted C₂ to C₈ alkenyl I10 —COOX₁₀ optionally R_(7a)COO—R_(2a)COO— O OH substituted C₂ to C₈ alkynyl I11 —COX₁₀ optionallyR_(7a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkynyl I12 —CONHX₁₀optionally R_(7a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkynyl J1—COOX₁₀ heterocyclo R_(7a)COO— R_(2a)COO— OH OH J2 —COX₁₀ heterocycloR_(7a)COO— R_(2a)COO— OH OH J3 —CONHX₁₀ heterocyclo R_(7a)COO—R_(2a)COO— OH OH J4 —COOX₁₀ optionally R_(7a)COO— R_(2a)COO— OH OHsubstituted C₂ to C₈ alkyl J5 —COX₁₀ optionally R_(7a)COO— R_(2a)COO— OHOH substituted C₂ to C₈ alkyl J6 —CONHX₁₀ optionally R_(7a)COO—R_(2a)COO— OH OH substituted C₂ to C₈ alkyl J7 —COOX₁₀ optionallyR_(7a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J8 —COX₁₀optionally R_(7a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J9—CONHX₁₀ optionally R_(7a)COO— R_(2a)COO— OH OH substituted C₂ to C₈alkenyl J10 —COOX₁₀ optionally R_(7a)COO— R_(2a)COO— OH OH substitutedC₂ to C₈ alkynyl J11 —COX₁₀ optionally R_(7a)COO— R_(2a)COO— OH OHsubstituted C₂ to C₈ alkynyl J12 —CONHX₁₀ optionally R_(7a)COO—R_(2a)COO— OH OH substituted C₂ to C₈ alkynyl K1 —COOX₁₀ heterocycloR_(7a)COO— R_(2a)COO— R_(9a)COO— OH K2 —COX₁₀ heterocyclo R_(7a)COO—R_(2a)COO— R_(9a)COO— OH K3 —CONHX₁₀ heterocyclo R_(7a)COO— R_(2a)COO—R_(9a)COO— OH K4 —COOX₁₀ optionally R_(7a)COO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkyl K5 —COX₁₀ optionally R_(7a)COO— R_(2a)COO—R_(9a)COO— OH substituted C₂ to C₈ alkyl K6 —CONHX₁₀ optionallyR_(7a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkyl K7—COOX₁₀ optionally R_(7a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ toC₈ alkenyl K8 —COX₁₀ optionally R_(7a)COO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkenyl K9 —CONHX₁₀ optionally R_(7a)COO—R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkenyl K10 —COOX₁₀optionally R_(7a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈alkynyl K11 —COX₁₀ optionally R_(7a)COO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkynyl K12 —CONHX₁₀ optionally R_(7a)COO—R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkynyl

EXAMPLE 5 In Vitro Cytotoxicity Measured by the Cell Colony FormationAssay

Four hundred cells (HCT116) were plated in 60 mm Petri dishes containing2.7 mL of medium (modified McCoy's 5a medium containing 10% fetal bovineserum and 100 units/mL penicillin and 100 g/mL streptomycin). The cellswere incubated in a CO₂ incubator at 37° C. for 5 h for attachment tothe bottom of Petri dishes. The compounds identified in Example 2 weremade up fresh in medium at ten times the final concentration, and then0.3 mL of this stock solution was added to the 2.7 mL of medium in thedish. The cells were then incubated with drugs for 72 h at 37° C. At theend of incubation the drug-containing media were decanted, the disheswere rinsed with 4 mL of Hank's Balance Salt Solution (HBSS), 5 mL offresh medium was added, and the dishes were returned to the incubatorfor colony formation. The cell colonies were counted using a colonycounter after incubation for 7 days. Cell survival was calculated andthe values of ID50 (the drug concentration producing 50% inhibition ofcolony formation) were determined for each tested compound.

IN VITRO Compound ID 50 (nm) HCT116 taxol 2.1 docetaxel 0.6 1351 <1 1364<10 1372 26.1 1386 <1 1393 <1 1401 <1 1418 <1 1424 <1 1434 <10 1447 <101458 <10 3069 <1 3082 <1 3171 <1 3196 <10 3232 <1 3327 <10 3388 <10 3444<1 3479 <1 3555 <10 3560 <1 3611 <1 3629 <1 3632 <1 3708 <1 3713 <104017 <10 4044 <1 4106 <10 4135 <1 4175 <10 4219 29.0 4256 <1 4283 <14290 <10 4312 <1 4388 <1 4394 <1 4406 <1 4446 <1 4499 <1 4544 <10 4600<10 4616 <1 4737 <1 4757 <1 6171 <10 6131 <1 5989 <10 6141 <1 6181 <16040 <10 6121 <10 6424 21.7 6212 <1 6282 <10 6252 <1 6343 <10 6272 <16202 <1 4454 <1 4414 <1 6333 <1 6686 <1 6363 <10 4787 <10 4828 <10 4898<1 4939 <1 5020 <1 5030 <1 5191 <10 5202 <10 5070 <10 5080 <1 5121 21.15131 <10

EXAMPLE 6 Preparation of Solutions for Oral Administration

Solution 1: Antitumor compound 1393 was dissolved in ethanol to form asolution containing 140 mg of the compound per ml of solution. An equalvolume of Cremophor® EL solution was added to the solution whilestirring to form a solution containing 70 mg of compound 1393 per ml.This solution was diluted using 9 parts by weight of saline to form apharmaceutically acceptable solution for administration to a patient.

Solution 2: Antitumor compound 1458 was dissolved in ethanol to form asolution containing 310 mg of the compound per ml of solution. An equalvolume of Cremophor® EL solution was added to the solution whilestirring to form a solution containing 155 mg of compound 1458 per ml.This solution was diluted using 9 parts by weight of saline to form apharmaceutically acceptable solution for administration to a patient.

Solution 3: Antitumor compound 1351 was dissolved in ethanol to form asolution containing 145 mg of the compound per ml of solution. An equalvolume of Cremophor® EL solution was added to the solution whilestirring to form a solution containing 72.5 mg of compound 1351 per ml.This solution was diluted using 9 parts by weight of saline to form apharmaceutically acceptable solution for administration to a patient.

Solution 4: Antitumor compound 4017 was dissolved in ethanol to form asolution containing 214 mg of the compound per ml of solution. An equalvolume of Cremophor® EL solution was added to the solution whilestirring to form a solution containing 107 mg of compound 4017 per ml.This solution was diluted using 9 parts by weight of saline to form apharmaceutically acceptable solution for administration to a patient.

Solution 5: Antitumor compound 1393 was dissolved in 100% ethanol thenmixed with an equal volume of Cremophor® EL solution to form a solutioncontaining 70 mg of compound 1393 per ml. This solution was dilutedusing 9 parts by weight of D % W (an aqueous solution containing 5%weight by volume of dextrose) or 0.9% saline to form a pharmaceuticallyacceptable solution for administration to a patient.

EXAMPLE 7 Preparation of a Suspension Containing Compound 1393 for OralAdministration

An oral composition of antitumor compound 1393 was prepared bysuspending 25 mg of compound 1393 as a fine powder in one ml of carriercontaining 1% carboxymethylcellulose (CMC) in deionized water.

EXAMPLE 8 Preparation of a Tablet Containing Compound 1393 for OralAdministration

Antitumor compound 1393 (100 mg) was dissolved in methylene chloride (2ml) and Cremophor® EL solution (100 mg) was added. The methylenechloride was evaporated under vacuum to form a glass. Microcrystallinecellulose (600 mg) was added to the glass and mixed to form a powderwhich can be processed to form a tablet.

EXAMPLE 9 Preparation of Emulsions Containing Compound 1393 forParenteral Administration

Emulsion 1: Antitumor compound 1393 was dissolved in 100% ethanol toform a solution containing 40 mg of compound 1393 per ml of thesolution. The solution was then diluted with 19 parts by weight ofLiposyn® II (20%) with stirring to form an emulsion containing 2 mg ofcompound 1393 per ml for parenteral administration.

Emulsion 2: Antitumor compound 1393 was dissolved in 100% ethanol toform a solution containing 40 mg of compound 1393 per ml of thesolution. The solution was then diluted with 19 parts by weight ofLiposyn® III (2%) with stirring to form an emulsion containing 2 mg ofcompound 1393 per ml for parenteral administration.

Emulsion 3: Antitumor compound 1393 was dissolved in 100% ethanol toform a solution containing mg of compound 1393 per ml of the solution.The solution was then diluted with 9 parts by weight of Liposyn® III(2%) with stirring to form an emulsion containing 4 mg of compound 1393per ml for parenteral administration.

EXAMPLE 10 Preparation of Solutions Containing Compound 1393 forParenteral Administration

Solution 1: Antitumor compound 1393 was dissolved in 100% ethanol toform a solution containing 140 mg of compound 1393 per ml. The solutionwas then diluted with an equal volume of Cremophor® EL solution withstirring and was then diluted with 9 parts by weight of normal saline toform a solution containing 7 mg of compound 1393 per ml of solution forparenteral administration.

Solution 2: Antitumor compound 1393 was dissolved in 100% ethanol toform a solution containing 140 mg of compound 1393 per ml of thesolution. The solution was then diluted with an equal volume ofCremophor® EL solution with stirring and was then diluted with 4 partsby weight of normal saline to form a solution containing 11.7 mg ofcompound 1393 per ml of solution for parenteral administration.

Solution 3: Antitumor compound 1393 was dissolved in 100% ethanol toform a solution containing 140 mg of compound 1393 per ml of thesolution. The solution was then diluted with an equal volume ofCremophor® EL solution with stirring and was then diluted with 2.33parts by weight of normal saline to form a solution containing 16.2 mgof compound 1393 per ml of solution for parenteral administration.

What is claimed is:
 1. A taxane having the formula

wherein R₂ is benzoyloxy; R₇ is propionyloxy; R₁₀ is hydroxy; X₃ isfuryl or thienyl; X₅ is —COOX₁₀; X₁₀ is t-butyl; and Ac is acetyl. 2.The taxane of claim 1 wherein X₃ is furyl.
 3. The taxane of claim 2wherein X₃ is 2-furyl.
 4. The taxane of claim 2 wherein X₃ is 3-furyl.5. The taxane of claim 1 wherein X₃ is thienyl.
 6. The taxane of claim 5wherein X₃ is 2-thienyl.
 7. The taxane of claim 6 wherein X₃ is3-thienyl.